Project 3, a new SPORE project initiated using Developmental Research Program support in the present SPORE, will utilize the state-of-the-art Bruker ClinProtTM Ultraflexll MALDI TOF/TOF mass spectrometry (MS) and Luminex multianalyte (LabMAP(R)) systems to profile serum samples from an extensive population of SPORE accrued lung cancer patients and controls. First we will develop a panel of proteomic MS features reproducibly detectable in serum together with optimized panels of known serum analytes relevant to lung cancer including cytokines, chemokines, growth/angiogenesis factors and receptors, and lung specific biomarkers, to provide robust detection and discrimination of lung cancer. This combined MS/LabMAP(R) serum proteomic panel and predictive lung cancer model will then be tested in an independent series of case/controls sera in collaboration with the Vanderbilt Lung SPORE and in a series of screening CT-detected lung Cancers in the UPCI SPORE PLuSS cohort. The refined MS/ LabMAP(R) panel and predictive model will be tested in a prospectively collected series of serum samples from subjects in the PLuSS High-Risk Sub-Cohort subsequently diagnosed with a newly-incident CT-detected lung cancer during a 5-year active follow-up. To test the power of this proteomic approach to predict lung cancer recurrence, the UPCI case series will be followed prospectively by the SPORE Clinical Core for recurrence, disease progression, and survival. The baseline MALDI-TOF-MS proteomic profiles and MS/LabMAP(R) panel will then be evaluated and a model constructed to predict these clinical outcomes. The predictive recurrence model will then be tested in the Vanderbilt Lung Cancer SPORE cases. Lastly, in parallel with these aims, diagnostic MS features ("peaks") will be investigated for peptide/protein identification using a suite of biochemical enrichment/fractionation and MS analytical methods for lung cancer biomarker discovery. The translational goals of Project 3 are to develop a MS/LabMAP(R) serum profile and predictive algorithm to provide improved diagnosis of patients presenting with clinical symptoms or radiographic findings suspicious for lung cancer;to improve early detection of lung cancer by identifying a MS/LabMAP(R) serum profile in high-risk subjects prior to the clinical diagnosis of a lung malignancy by screening CT;and the application of MS/LabMAP(R) serum profiling for prediction and early detection of lung cancer recurrence.